key: cord-0683075-msywiw4z authors: Kumar, Rakesh; Kumar, Rahul; Goel, Harsh; Tanwar, Pranay title: Computational investigation reveals that the mutant strains of SARS-CoV2 are highly infectious than wildtype date: 2021-04-23 journal: bioRxiv DOI: 10.1101/2021.04.23.441125 sha: 01768150c1cd10af56cf16996673ae326aed6897 doc_id: 683075 cord_uid: msywiw4z Remarkable infectivity of severe acute respiratory syndrome-coronavirus 2 (SARS-CoV2) is due to the rapid emergence of various strains, thus enable the virus to rule the world. Over the course of SARS-CoV2 pandemic, the scientific communities worldwide are responding to newly emerging genetic variants. However, the mechanism behind the persistent infection of these variants is still not known due to the paucity of study of these variants at molecular level. In this scenario, computational methods have immense utility in understanding the molecular and functional properties of different variants. Therefore, in this study various mutants (MTs) of SpikeS1 receptor binding domain (RBD) of highly infectious SARS-CoV2 strains were carried and elucidated the protein structure and dynamics using molecular dynamics (MD) approach. MD simulation study showed that all MTs exhibited stable structures with altered functional properties. Furthermore, the binding strength of different MTs along with WT (wildtype) was revealed through protein-protein docking and observed that MTs showed high binding affinities than WT. Hence, this study shed light on the molecular basis of infection caused by different variants of SARS-CoV2, which might play an important role in to cease the transmission and pathogenesis of virus and also implicate in rational designing of a specific drug. of the host ACE2 receptor (Lan et al., 2020) . The rest of mutations V367F and R408I, mostly 128 affected the overall topology and stability of RBD as these mutations present at the loop 129 regions of N-terminal and turn that connect β-sheet3 and 4, respectively (Yan et al., 2020) . 130 These mutations (V367F, R408I, G476S, V483A and N501Y) indirectly assist in the stable 131 binding of RBD to the host ACE2 receptor (Lan et al., 2020) . In addition to the above The tertiary structure of RBD of Spike S1 protein was taken from RCSB-PDB (Research 147 collaboration for structural bioinformatics-protein data bank), which was experimentally Ramachandran plot and found that all 3D structures exhibited 68.5%, 29.5% and 2% of 258 residues to be placed in favourable, allowed and disallowed regions, respectively (Table S3) . and QMEAN values ranging from -5.15 to -5.25 and -7.33 to -8.15, respectively (Table S3) . V483A, and N501Y MTs, respectively (Fig. 4A & B) . Moreover, we found a similar pattern 344 of fluctuations in PC1, PC2, and PC3 as we found during RMSF analysis (Fig. S6) when projecting the PC1 vs PC3 and PC2 vs PC3 in phase space (Fig. S7) . The above results showed that N501Y mutant undergoes large conformational changes. The conformational changes at the structural level were further elucidated by sequentially 355 superimposing the 30 frames of first PC for all WT and MTs (Fig. 5) . higher CB values (Fig. 6F) . Interestingly, all residues except Y453 lies at the loop region of (Table 2) . Additionally, all p-p complexes were stabilised by the 403 ample amount of hydrophilic as well as hydrophobic interactions (Figs. S10&S11; Table S6 ). Furthermore, p-p binding free energies were also verified through the change in binding 405 affinities of ACE2-WT and -MT complexes by using mCSM-PPI server and we found that shown as blue and red colour, respectively. Amino acid residues were depicted in stick 716 mode with 3-letter code. WT, V367F, R408I, G476S, V483A and N501Y MTs were 717 labelled in black, red, green, blue, magenta and yellow colour, respectively. were labelled in black, red, green, blue, magenta and yellow colour, respectively. Essential dynamics of 558 proteins Sequence and structural patterns 560 detected in entangled proteins reveal the importance of co-translational folding QMEAN: A comprehensive scoring 563 function for model quality assessment Collective protein dynamics in relation to 566 function The europe second wave of COVID-19 infection and the Italy 568 "strange" situation I-Mutant2. 0: predicting stability changes 570 upon mutation from the protein sequence or structure NAPS: network analysis of protein 573 structures 576 translationally controlled tumor protein (TCTP): insights from molecular 611 dynamics Structure of the SARS-CoV-2 spike receptor-binding domain bound 614 to the ACE2 receptor LigPlot+: multiple ligand-protein 616 interaction diagrams for drug discovery Molecular Mechanism of the N501Y Mutation 619 for Enhanced Binding between SARS-CoV-2's Spike Protein and Human ACE2 Assessment of protein models with three-622 dimensional profiles AMPKα promotes basal autophagy induction 624 in Dictyostelium discoideum SARS-like WIV1-CoV poised for human emergence COVID-19 pandemic: Insights into structure, function, and hACE2 receptor recognition 632 by SARS-CoV-2 Mutant strains of SARS-CoV-2 are 634 more prone to infect obese patient: a review A biomolecular 636 force field based on the free enthalpy of hydration and solvation: the GROMOS force-field 637 parameter sets 53A5 and 53A6 Contribution of hydrogen bonds to protein stability Functional topology in a network of protein 642 interactions predicting the effects of mutations on protein-protein interactions The RCSB Protein Data Bank: redesigned web 649 site and web services Coronavirus pandemic 651 (COVID-19). Our world in data A virus that 653 has gone viral: amino acid mutation in S protein of Indian isolate of Coronavirus COVID-654 19 might impact receptor binding, and thus, infectivity Deep Mutational Scanning of SARS-CoV-2 Receptor Binding Domain Reveals 658 Constraints on Folding and ACE2 Binding On the origin and 660 continuing evolution of SARS-CoV-2 Emergence and rapid spread of a new severe acute respiratory 663 syndrome-related coronavirus 2 (SARS-CoV-2) lineage with multiple spike mutations in 664 South Africa GROMACS: fast, flexible, and free User-Friendly Integrative Modeling of Biomolecular Complexes A novel coronavirus 673 outbreak of global health concern SARS-CoV-2 mutations in the United States suggests presence of four substrains and 676 novelvariants Covid-19: New coronavirus variant is identified in UK The SARS-Coronavirus Infection Cycle: A Survey 683 of Viral Membrane Proteins, Their Functional Interactions and Pathogenesis Genome 687 Composition and Divergence of the Novel Coronavirus (2019-nCoV Structural basis for the 690 recognition of SARS-CoV-2 by full-length human ACE2 Molecular interaction and inhibition 693 of SARS-CoV-2 binding to the ACE2 receptor Effects of a major deletion in the SARS-CoV-2 genome on the severity of infection and 698 the inflammatory response: an observational cohort study Tertiary structure, RMSD and Rg analyses. (A) Tertiary structure of SpikeS1 RBD of 703 Root mean square deviation at function of time and (C) Radius of 704 gyration at function of time in nanoseconds. 3D structure of RBD was shown in cartoon 705 mode with cyan colour and different mutations V367F, R408I, G476S, V483A and N501Y 706 were depicted in stick mode. Region interacting with host ACE2 of SpikeS1 RBD and 707 extended loop were highlighted in back and blue dotted circles, respectively Root mean square fluctuation (RMSF) analysis. (A) RMSF plot at function of amino 711 acid residues, (B) Structure fluctuations of WT